Phosphorus prodrugs

Abstract

The composition and methods of synthesis of phosphorus prodrugs are described. These methods can be used to convert negatively charged phosphorous bearing drugs into neutrally charged; lipid soluble prodrugs which are able to passively diffuse into cells and into tissues in vivo. Prodrugs for a variety of antiviral and anti-leukemic agents are described.

I claim: 
     
       1. A compound represented by the following structural formula: ##STR31## wherein: R 1  is a (--OCOR 14 ) group; a (--O--CO--O--R 14 ) group; a (--O--CO--NHCH 3 ) group; or a (--O--CO--N(CH 3 ) 2 ) group; R 2  and R 7  are independently hydrogen, a (--CO 2  R 10 ) group; a methyl group; a halogen; a methoxy group; a (--O--CO--R 8 ) group, or a hydroxymethyl group (HO--CH 2  --);   R 3  and R 6  are independently hydrogen; a methyl group, a hydroxymethyl group (--CH 2  --OH); --COOR 9  ; a halogen; a hydroxyethyl group (--CH 2  --CH 2  --OH); --CH 2  CO 2  R 11  ; or --CF 3  ;   R 8  is a C1 to C31 straight chained alkyl group, isopropyl, t-butyl, a phenyl group or a group such that (H--O--CO--R 8 ) is an amino acid, lactic acid, glycolic acid, acetoacetic acid;   R 9 , R 10 , R 11  and R 12  are independently a methyl, ethyl, phenyl or benzyl group;   R 14  is a C1-C31 straight chain alkyl group, --O--(C1-C31 straight chain group), isopropyl, --O-isopropyl, t-butyl, --O--(t-butyl), phenyl, --O-phenyl, --NHCH 3 , --N(CH 3 ) 2  or R 14  can be selected such that R 14  --CO 2  H is an amino acid; lactic acid; glycolic acid (--HO--CH 2  --CO 2  H); glyceric acid (HO--CH 2  --CH(OH)--CO 2  H); or acetoacetic acid (CH 3  COCH 2  --CO 2  H).   
     
     
       2. A compound of claim 1 of the following structure: ##STR32## wherein R 12  is methyl or ethyl and R 8  is methyl or t-butyl. 
     
     
       3. A compound represented by the following structural formula: ##STR33## wherein: R 1  is a (--OCOR 14 ) group; a (--O--CO--O--R 14 ) group; a (--O--CO--NHCH 3 ) group; or a (--O--CO--N(CH 3 ) 2 ) group; R 2  and R 7  are independently hydrogen; a (--CO 2  R 10 ) group; a C1--C31 straight chained alkyl group; isopropyl; t-butyl; a halogen; --O--(C1-C31 straight chained alkyl group); --O--(isopropyl); --O--(t-butyl); a (--O--CO--R 8 ) group; or a hydroxymethyl group (HO--CH 2 );   R 3  and R 6  are independently hydrogen; a C1-C31 straight chained alkyl group; isopropyl; t-butyl; a (--CO 2  R 9 ) group; a hydroxymethyl group (--CH 2  --OH); a halogen; a hydroxyethyl group (--CH 2  --CH 2  --OH); a --CH 2  CO 2  R 11  group; or --CF 3  ;   R 8  is a C1-C31 straight chain alkyl group, isopropyl or t-butyl; a substituted or unsubstituted phenyl group, or a group such that (H--O--CO--R 8 ) is an amino acid, lactic acid, glycolic acid, acetoacetic acid;   R 9 , R 10 , R 11  and R 12  are independently a C1-C30 straight chain alkyl group, an isopropyl group or a t-butyl group; a phenyl group, a substituted phenyl group, a benzyl group or a substituted benzyl group;   R 14  is a C1-C31 straight chain alkyl group, --O--(C1-C31 straight chain group), isopropyl, --O-isopropyl, t-butyl, --O--(t-butyl), phenyl, --O-phenyl, a substituted phenyl group, --O--(substituted phenyl), --NHCH 3 , --N(CH 3 ) 2  or R 14  can be selected such that R 14  --CO 2  H is; an amino acid; lactic acid; glycolic acid (--HO--CH 2  --CO 2  H); glyceric acid (HO--CH 2  --CH(OH)--CO 2  H); or acetoacetic acid (CH 3  COCH 2  --CO 2  H).